Method of producing a depressant effect using 5-cyclopropyl-1,2,4-oxadiazol-3-yl diazines

ABSTRACT

Preparation of 1,2,4-oxadiazolyldiazines by the reaction of cyclopropylcarboxylic acid anhydride and a diazinecarboxamidoxime at an elevated temperature. Other methods are also described. The compounds are useful for their central nervous system depressant activity.

United States Patent [1 1 F anshawe et al.

[ METHOD OF PRODUCING A DEPRESSANT EFFECT USING S-CYCLOPROPYL- l ,2,4-OXADlAZOL-3-YL DIAZINES [75] Inventors: William Joseph Fanshawe, Pearl River, N.Y.; Sidney Robert Safir, River Edge, NJ.

[73] Assignee: American Cyanamid Company,

Stamford, Conn.

[22] Filed: Aug. 20, 1974 [21] App]. No.: 498,902

Related U.S. Application Data [60] Continuation-impart of Scr. No. 347,307, April 2, 1973, Pat. No. 3,857,843, which is a division of Ser. No. 288,219, Sept. 1 l, 1972, Pat. No. 3,770,739.

[52] U.S. Cl 424/250; 424/251 [51] Int. Cl. A6IK 31/495; A61K 31/505 [451 Sept. 16, 1975 [58] Field of Search 424/250, 251

[56] References Cited OTHER PUBLICATIONS Wiley, etc.: Heterocyclic Compounds, Five and Six Membered Compounds With Oxygen and Nitrogen (1962), P. 245.

Primary ExaminerStanley J. Friedman Attorney, Agent, or Firm-Emest Y. Miller METHOD ()F PRODUCING A DEPRESSANT EFFECT USING S-CYCLOPROPYL-1,2,4-OXADIAZOL-3-YL DIAZINES Y DESCRIPTION OF THE INVENTION This invention relates to a method of using compositions containing l,2,4oxadiazolyldiazines which 'component may be illustrated by the following formula:

wherein R is selected from the group consisting of pyrazinyl, pyridazinyl and pyrimidyl; Z'is a trivalent radical selected from the group consisting of II I I ll NO and ON and the dotted line represents one double bond, the position of which is dependent upon the definition of Z. When Z is the double bond is between N and carbon containing the R substituent and when Z has the other meaning, the double bond is in the other position.

Pharmaceutically acceptable acid addition salts of the active components are considered to be within the purview of the present invention and can be prepared by direct neutralization of the free base with theappropriate acid. These salts are those in which the anion does not contribute significant toxicity to the salt in the dosages thereof employed in accordance with the present invention. Examples of suitable salts are the acetate, propionate, butyrate, pamoate, mucate, citrate, malate, tosylate, phosphate, nitrate, sulfate, hydrobromide, hydroiodide, hydrochloride, etc.

:2 The present active components are somewhat soluble in hydrocarbon solvents. The salts of the components are slightly soluble in water.

The active components of the present invention can be prepared by reaction of cyclopropylcarboxylic acid anhydride and a diazinecarboxamidoxime at elevated temperature inxthe presence or absence of a solvent. The components are also prepared by the reaction of a diazinecarboxylic acid chloride or of anester of a diazinecarboxylic acid with cyclopropylcarboxamidoxime in the presence of solvent at an elevated temperature.

These reactions are illustrated schematically below:

HON

The compositions of this invention show central nervous system depressant activity by their ability to protect warm-blooded animals, e.g., mice, from convulsions and lethality resulting from the administration of strychnine sulfate [H. M. Hanson and C. A. Stone, Animal and Clinical Pharmacological Techniques in Drug Evaluation, Vol. I, J. H. Nodine and P, E. Siegler, Eds. Yearbook Medical Publishers, Inc., Chicago. Ill., 1964, p. 317]. Graded dose levels of the compounds are administered intraperitoneally in a 27: aqueous starch medium to groups of ten mice at each dosev Strychnine sulfate, dissolved in aqueous saline is administered subcutaneously 30 minutes after drug treatment at a dose estimated to cause death in 9571 of the mice; namely, 1.25 mg. per kilogram of. body weight. The medium effective does is calculated by the method of J. T. Litchfield and F. Wilcoxon [J. Pharmacol. Exp. Ther., 96, 99 (1949)]. These data on representative compounds of this invention are summarized in Table I. It has been reported [M. I. Gluckman, Pharmacology of ,oxazepam (Serax) an antianxiety agent, Curr. Therap. Res., 1 721 (1965)] that there is a high degree of correlation between anticonvulsant effects in mice and antianxiety effects in higher warmblooded animals. The following table shows the activity of representative active components of this invention.

TABLE Protection Against Death Caused by Strychnine Sulfate in Mice Median Effective Dose (mg/kg. intraperitoneally for protection versus death caused by strychnine Compound 2-( -cyclopropyl- 3.5 l ,2,4-oxadiazol- 4-(5-cyclo- 6.0

propyll ,2,4- oxadiazol-3-yl pyriduzine 4-(5-cyclopropyl- 27 1,2,4-oxadiazol- 3-yl )pyrimidine 2-( 3-cyclopropyl- 39 1,2 ,4-oxadiazol- 5-yl )pyrazine The present active components may be dispensed in the form of capsules, tablets, pills, powders, dispersible granules and cachets. One or more of the following may act as solid pharmaceutical carrier flavoring agents, binders, tablet disintegrating agents, encapsulating material and the like. Other solid carriers can be, for example, magnesium carbonate or stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellu lose, etc. Preferably, the active component may represent a major portion of the dosage unit. The present compounds may 'be used in dosages which range from about 0.1 to 100 mg./kg./per day in warm-blooded animals. The warm-blooded animals. The warm-blooded animals may include mice, rats, guinea pigs dogs, rabbits, sheep, etc. A dosage unit may range from to 150 mg. given one or more times per day. It is usually preferable to give more than one dosage unit per day at predetermined intervals.

DETAILED DESCRIPTION The examples which follow describe the preparation of representative active components of the present invention and their use in representative compositions.

EXAMPLE 1 Preparation of 2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)pyrazine A mixture of 6.9 g. of pyrazinecarboxamidoxime and 7.7 g. of cyclopropanecarboxylic acid anhydride in 100 ml. of xylene is heated under reflux for 3 hours. The xylene is evaporated under reduced pressure and the residue is suspended in aqueous sodium carbonate. The mixture is filtered to collect tan crystals which are recrystallized from isopropyl alcohol to give straw-col- 4 ored crystals, melting point 9598C The compound forms a slightly water soluble hydrochloride salt.

EXAMPLE 2 Preparation' of 2-(5-methyl-l ,2,4-oxadiaz'ol-3-yl )pyrazine A stirred mixture of 2.8 g. of pyrazinecarboxamidoxime and 2.0 g. of acetic anhydride in 50 ml. of xylene is 0 heated under reflux for 3 hours. The xylene is evaporated under reduced pressure and the residue is recrystallized twice from isopropyl alcohol to give white crystals, melting point lOOlO4C.

EXAMPLE 3 Preparation of 2-( S-ethyll ,2,4-oxadiazol-3-yl )pyrazine A stirred mixture of 2.8 g. of pyrazinecarboxamidoxime and 2.6 g. of propionic anhydride in 50 ml. of xylene is heated under reflux for 3 hours and concentrated to a viscous liquid. The liquid is suspended in aqueous sodium carbonate and the mixture is extracted with chloroform. The chloroform solution is dried over anhydrous mangesium sulfate and concentrated to a solid. Recrystallization from hexane gives white crystals, melting point 5257C.

EXAMPLE 4 Preparation of 4-( S-Cyclopropyl- 1 ,2,4-oxadiazol-3-yl )pyridazine EXAMPLE 5 Preparation of 4-( 5-ethyl- 1 ,2,4-oxadiazol-3-yl )pyridazine A mixture of 0.92 g. of 4-pyridazinecarboxamidoxime, 1.05 g. of propionic anhydride and 20 ml. of xylene is heated under reflux for 2 hours. The mixture is washed in 1 N sodium hydroxide, the xylene solution dried over mangesium sulfate and concentrated to give a tan solid. This solid is recrystallized from cyclohexane to give colorless needles, melting point 73-74C.

EXAMPLE 6 Preparation of 4-( S-cyclopropyl- 1 ,2,4-oxadiazol-3-yl)pyrimidine A mixture of 1.4 g. of 4-pyrimidinecarboxamidoxime and 1.5 g. of cyclopropanecarboxylic acid anhydride in 20 ml. of xylene is heated under reflux for 3 hours. The mixture is concentrated to give a viscous, orange liquid which is suspended in aqueous sodium carbonate and then filtered to collect an orange solid. This solid is recrystallized from cyclohexane to give pale yellow crystals, melting point 8994C. The compound forms a sparingly water soluble citrate salt.

EXAMPLE 7 Preparation of 2-( 3-Cyclopropyl-l ,2,4-oxadiazol-5-yl )pyrazine To a mixture of 28.7 g. of pyrazinoyl chloride in 100 ml. of xylene is added slowly a solution of g. of cyclopropanecarboxamidoxime in 100 ml. of xylene. This mixture is heated under reflux for 3 hours, concen trated under reduced pressure and the residue mixed with aqueous sodium hydroxide. The mixture is filtered and the filtrate is extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to give crude crystals, which are recrystallized from cyclohexane to give light yellow crystals, melting point 6l64C.

EXAMPLE 8 Preparation of 2-( 3-Cyclopropyll ,2,4-oxadiazol-5-yl )pyrazine To a mixture of 2.8 g. of cyclopropanecarboxamidoxime hydrochloride and 2.8 g. of methyl pyrazinoate in 50 ml. of toluene is added 2.2 g. of sodium methoxide. The mixture is heated under reflux for 30 minutes and then poured into 100 ml. of water. The toluene phase is separated and the aqueous phase is extracted with chloroform. The combined organic solutions are dried over magnesium sulfate and concentrated under reduced pressure to give a solid. This solid is recrystallized from cyclohexane to give cream-colored crystals, melting point 6668C. The compound forms a slightly water soluble phosphate salt, when treated with phosphoric acid.

EXAMPLE 9 Tablets containing the present active components can be prepared as follows:

Magnesium stcaratc The above ingredients are thoroughly mixed and incorporated into 1000 standard pharmaceutical tablets. Each tablet contains lOO mg. of active component.

EXAMPLE 10 Compositions containing the active components of the invention as capsules can be prepared from the following formulation:

Grams 4-(5-cyclopropyll 2,4 lO0.0 oxadiazol-3-yl )pyrimidine Lactose 450.0 Magnesium stearate 5.0

wherein Z is a trivalent radical selected from the group consisting of ll I I ll N-O and O-N;

the dotted line represents one double bond, the position being dependent upon the definition of Z; R is selected from the group consisting of pyrazinyl, pyridazinyl and pyrimidyl or a pharmaceutically acceptable salt thereof.

2. A method in accordance with claim 1, wherein the cyclopropyl-1,2,4-oxadiazolyldiazine is 2-(5-cyclopropyl-l ,2,4-oxadiazol-3-yl )pyrazine.

3. A method in accordance with claim 1, wherein the cyclopropyl-l ,2,4-oxadiazolyldiazine is 4-(5-cyclopropyl-l ,2,4-oxadiazol-3-yl )pyrimidine.

4. A method in accordance with claim 1, wherein the cyclopropyl-1,2,4-oxadiazolyldiazine is 4-(5-cyclopropyl-l ,2,4-oxadiazol-3-yl )pyridazine.

5. A method in accordance with claim 1, wherein the cyclopropyll ,2,4-oxadiazolyldiazine is administered at from 0.1 to mgJkg/per day. 

1. A METHOD OF PRODUCING A DEPRESSANT EFFECT IN A WARMBLODDED ANIMAL WHICH COMPRISES ORALLY ADMINISTRATING TO SAID ANIMAL A DEPRESSANT EFFECTIVE AMOUNT OF A CYCLOPROPYL-1,2,4OXADIAZOLYLDIAZINE OF THE FORMULA:
 2. A method in accordance with claim 1, wherein the cyclopropyl-1,2,4-oxadiazolyldiazine is 2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)pyrazine.
 3. A method in accordance with claim 1, wherein the cyclopropyl-1,2,4-oxadiazolyldiazine is 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)pyrimidine.
 4. A method in accordance with claim 1, wherein the cyclopropyl-1,2,4-oxadiazolyldiazine is 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)pyridazine.
 5. A method in accordance with claim 1, wherein the cyclopropyl-1,2,4-oxadiazolyldiazine is administered at from 0.1 to 100 mg./kg./per day. 